Dihydropyrimidines and uses thereof

• US 6,228,861 B1
• Filed: 11/10/1998
• Issued: 05/08/2001
• Est. Priority Date: 11/16/1995
• Status: Expired due to Fees

• Current Assignee: H. Lundbeck A/S (Lundbeck Foundation)
• Original Assignee: Synaptic Pharmaceutical Corporation (Lundbeck Foundation)
• Inventors: Nagarathnam, Dhanapalan, Patane, Michael A., Gluchowski, Charles, Wong, Wai C., Miao, Shou Wu
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Rao, Deepak R.
• Application Number:
  US09/068,782
• Time in Patent Office: 910 Days
• Field of Search: 544/311, 544/317, 544/318, 514/372
• US Class Current: 514/272
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 239/22 with hetero atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

This invention is directed to dihydropyrimidine compounds which are selective antagonists for human α_1A receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where the antagonism of the α_1A receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

Claims

1. A compound having the structure:

where M has the structure

wherein each of Y₁, Y₂, Y₃, Y₄ and Y₅ independently may be —

H;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

—

F, —

Cl, —

Br, or —

I;

—

NO₂;

—

N(R₃)₂;

—

N₃;

—

CN;

—

OR₃;

—

OCOR₃;

—

COR₃;

—

CON(R₃)₂;

or —

CO₂R₃;

or wherein two of Y₁, Y₂, Y₃, Y₄ and Y₅ are present on adjacent carbon atoms and together constitute a methylenedioxy group;

where R independently may be —

H;

—

F;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

—

N(R₃)₂;

NO₂;

—

CN;

—

CO₂R₃;

—

(CH₂)_pPO(OR₃)₂;

—

(CH₂)_pPO(OR₃)₃;

or OR₃;

where R₁ may be —

H;

—

NO₂;

—

CN;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

—

N(R₃)₂;

—

OR₃;

—

(CH₂)_pOR₃;

—

COR₃;

—

CO₂R₃;

or —

CON (R₃)₂;

wherein any p independently is an integer from 1 to 7 inclusive;

where R₂ may be —

H;

straight chained or branched C₁-C₇ alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

C₃-C₁₀ cycloalkyl-C₁-C₁₀-alkyl, C₃-C₁₀ cycloalkyl-C₁-C₁₀-monofluoroalkyl or C₃-C₁₀ cycloalkyl-C₁-C₁₀-polyfluoroalkyl;

—

CN;

—

CH₂XR₃, —

CH₂X(CH₂)_pNHR₃, —

(CH₂)_nNHR₃, —

CH₂X(CH₂)_pN(R₃)₂, —

CH₂X(CH₂)_pN₃, or —

CH₂X(CH₂)_pNHCXR₇;

or —

OR₃;

wherein any n independently is an integer from 0 to 5 inclusive and p is as defined above;

where each R₃ independently may be —

H;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

—

(CH₂)_pPO(OR₈)₂;

—

(CH₂)_pPO(OR)₃;

or —

(CH₂)_pCOOR₈;

where R₄ has the structure

wherein Z may be C₂-C₇ alkenyl or alkynyl;

CH₂;

O;

CO;

CO₂;

CONR₃CO;

CONR₃;

S;

SO;

SO₂;

or NR₃;

m is an integer from 0 to 3 inclusive;

R₅ and R₆ each independently may be —

H;

—

;

—

Cl;

—

Br;

—

I;

—

CO₂R₃;

—

COR₃;

—

CON(R₃)₂;

—

CN;

—

NO₂;

—

N(R₃)₂;

—

OR₃;

straight chained or branched C₁-C₇ alkyl, C₁-C₇ monofluoroalkyl, C₁-C₇ polyfluoroalkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₇ cycloalkyl, or C₃-C₇ cycloalkenyl;

wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl may be unsubstituted or substituted with —

H, aryl, or heteroaryl;

aryl or heteroaryl wherein the aryl or heteroaryl may be unsubstituted or substituted with —

H, —

F, —

Cl, —

Br, —

I, —

NO₂, —

CN, —

N(R₃)₂, —

OR₃, —

COR₃, —

CO₂R₃, or —

CON(R₃)₂;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

R₇ may be —

H;

straight chained or branched C₁-C₇ alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

—

CN;

—

CO₂R₃;

—

COR₃;

—

CON(R₃)₂;

or —

OR₃;

where R₈ is —

H;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

where R₉ may be —

H;

—

CN;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

—

N(R₃)₂;

—

OR₃;

—

(CH₂)_pOR₃;

—

COR₃;

—

CO₂R₃;

or —

CON(R₃)₂;

where X may be S;

O;

or NR₃; and

where B may be —

H;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl;

straight chained or branched C₂-C₇ alkenyl;

—

SCH₂C₆H₄OR₃;

—

(CH₂)_nC₆H₅;

—

CH₂X(CH₂)_nNHR₃;

—

(CH₂) _nNHR₃;

or —

OR₃;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound comprises the (+) enantiomer.

3. The compound of claim 1, wherein the compound comprises the (−

) enantiomer.

4. The compound of claim 1, wherein the compound is selected from the group consisting of:

5. The compound of claim 4, wherein R₄ is

and p is 2, 3 or 4.

6. The compound of claim 5, wherein R₄ is

7. The compound of claim 5, having the structure:

8. The compound of claim 7, wherein M is polyfluorophenyl and R₅ is substituted or unsubstituted phenyl or pyridyl.

9. The compound of claim 8, wherein R₁ is —

CO₂CH₃, —

COCH₃, or —

CONH₂;

R₂ is —

CH₂OCH₃, methyl or ethyl; and

R₆ is H, —

CN, or CO₂CH₃.

10. The compound of claim 6, wherein the compound is selected from the group consisting of:

11. The compound of claim 10, wherein the compound is the (+) enantiomer.

12. The compound of claim 10, wherein the compound is the (−

) enantiomer.

13. The compound of claim 6, having the structure:

14. The compound of claim 13, wherein M is polyfluorophenyl and R₅ is substituted or unsubstituted phenyl or pyridyl.

15. The compound of claim 14, wherein the compound is:

16. The compound of claim 15, wherein the compound is the (+) enantiomer.

17. The compound of claim 15, wherein the compound is the (−

) enantiomer.

19. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.

20. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 effective to treat benign prostatic hyperplasia.

21. A method of claim 20, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.

18. A compound having the structure:

where M has the structure

wherein each of Y₁, Y₂, Y₃, Y₄ and Y₅ independently may be —

H;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

—

F, —

Cl, —

Br, or —

I;

—

NO₂;

—

N(R₃)₂;

—

N₃;

—

CN;

—

OR₃;

—

OCOR₃;

—

COR₃;

—

CON(R₃)₂;

or —

CO₂R₃;

or wherein two of Y₁, Y₂, Y₃, Y₄ and Y₅ are present on adjacent carbon atoms and together constitute a methylenedioxy group;

where R independently may be —

H;

—

F;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

—

N(R₃)₂;

—

NO₂;

—

CN;

—

CO₂R₃;

—

(CH₂)_pPO(OR₃)₂;

—

(CH₂)_pPO(OR₃)₃;

or —

OR₃;

wherein any p independently is an integer from 1 to 7 inclusive;

where R₁ may be —

H;

—

NO₂;

—

CN;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

—

N(R₃)₂;

—

OR₃;

—

(CH₂)_pOR₃;

—

COR₃;

—

CO₂R₃;

or —

CON(R₃)₂;

where R₂ may be —

H;

straight chained or branched C₁-C₇ alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl;

or cycloalkenyl;

C₃-C₁₀ cycloalkyl-C₁-C₁₀-alkyl, C₃-C₁₀ cycloalkyl-C₁-C₁₀-monofluoroalkyl, or C₃-C₁₀ cycloalkyl-C₁-C₁₀-polyfluoroalkyl;

—

CN;

—

CH₂XR₃, —

CH₂X(CH₂)_pNHR₃, —

(CH₂) NHR₃, —

CH₂X(CH₂)_pN(R₃)₂, —

CH₂X (CH₂)_pN₃, or —

CH₂X(CH₂)_pNHCXR₇;

or —

OR₃;

where any n independently is an integer from 0 to 5 inclusive;

where each R₃ independently may be —

H;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

—

(CH₂)_pPO(OR₈)₂;

—

(CH₂)_pPO(OR₈)₃;

or —

(CH₂)_pCOOR₈;

where R₄ has the structure

wherein Z may be C₂-C₇ alkenyl or alkynyl;

CH₂;

O;

CO;

CO₂;

CONR₃CO;

CONR₃;

S;

SO;

SO₂;

or NR₃;

wherein R₅ and R₆ each independently may be —

H;

—

F;

—

Cl;

—

Br;

—

I;

—

CO₂R₃;

—

COR₃;

—

CON(R₃)₂;

—

CN;

—

NO₂;

—

N(R₃)₂;

—

OR₃;

straight chained or branched C₁-C₇ alkyl, C₁-C₇ monofluoroalkyl, C₁-C₇ polyfluoroalkyl, C₂-C₇ alkenyl, or C₂-C₇ alkynyl;

or C₃-C₇ cycloalkyl or cycloalkenyl;

wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl may be unsubstituted or substituted with —

H, aryl, or heteroaryl;

wherein the aryl or heteroaryl may be unsubstituted or substituted with —

H, —

F, —

Cl, —

Br, —

I, —

NO₂, —

CN, —

N(R₃)₂, —

OR₃, —

COR₃, —

CO₂R₃, or —

CON(R₃)₂;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

or C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

wherein R₇ may be —

H;

straight chained or branched C₁-C₇ alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl, or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl;

—

CN;

—

CO₂R₃;

—

COR₃;

—

CON(R₃)₂;

or —

OR;

wherein R₈ is —

H;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

or C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

where R₉ may be —

H;

—

CN;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl or polyfluoroalkyl;

straight chained or branched C₂-C₇ alkenyl or alkynyl;

C₃-C₇ cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

—

N(R₃)₂;

—

OR₃;

—

(CH₂)_pOR₃;

—

COR₃;

—

CO₂R₃;

or —

CON(R₃)₂;

where each X may independently be S;

O;

or NR₃; and

where B may be —

H;

straight chained or branched C₁-C₇ alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl;

straight chained or branched C₂-C₇ alkenyl;

—

SCH₂C₆H₄OR₃;

—

(CH₂)_nC₆H₅;

—

CH₂X(CH₂)_nNHR₃;

—

(CH₂)_nNHR₃;

or —

OR₃;

or a pharmaceutically acceptable salt thereof.